1. Field of the Invention
The present invention relates to drugs which contain 1,4-(diphenylalkyl)piperazine derivatives as active ingredients and are useful for the prevention or treatment of drug dependence due to drug abuse.
2. Background Art
Drug dependence is a functional adaptive condition of the central nervous system changed by interactions between living bodies and drugs. Drug dependence is classified as a psychological dependence wherein one depends on the psychological effects of drugs and has a physical dependence to avoid unpleasant bioreactions due to withdrawal (withdrawal symptoms). Symptoms always observed in drug dependence are psychological dependence on drugs which have been ingested and a strong impulse to demand the drugs (Pharmacia, 34, 900-904 (1998)).
A fear of drug dependence due to drug abuse is a serious social problem. There is not yet a direct therapy of the psychological dependence, which is the essence of drug dependence, and addiction, which is its symptom (Pharmacia, 34, 905-909 (1998)). An agonist therapy of cocaine and the like are actively being studied as a pharmacotherapy of drug dependence (Pharmacia, 34, 877-882 (1998)).
All the addicting drugs act on the central nervous system as main effects or side effects and are roughly classified as opioid analgesics, central nervous system depressants, central nervous system stimulators and psychotomimetics.
Examples of opioid analgesics are opium and morphine contained in it, heroin semisynthesized from morphine and synthetic narcotics such as pethidine and methadone having similar pharmacological actions and dependency to them, and antagonistic analgesics such as pentazocine and buprenorphine.
Examples of central nervous system depressants are hypnotics such as barbituric acid derivatives, methaqualone, benzodiazepine derivatives and chloral hydrate; antianxiety drugs such as meprobamate and benzodiazepine derivatives; organic solvents such as thinner, alcohols and the like.
Examples of central nervous system stimulators are cocaine, which is one of typical narcotics, stimulants such as amphetamines, anorexigenic agents such as phenmetrazine, stimulators such as methylphenidate and pipradrol and drugs contained in luxury goods such as nicotine and caffeine.
Examples of psychotomimetics are hallucinogens such as LSD, DOM (2-amino-1-2,5-dimethoxy-4-methyl)phenylpropane) and mescaline, PCP (phencyclidine or xe2x80x9cangel dustxe2x80x9d), cannabis and the like (xe2x80x9cNEW Pharmacologyxe2x80x9d, p. 606-611, Nankodo, 1989).
The addicting drugs are also classified according to the existence of crossing of their tolerance-dependency. Morphine type addicting drugs are exemplified by morphine, codeine, methadone, pethidine and the like. Barbiturate-alcohol type addicting drugs are exemplified by barbiturates, alcohols, weak tranquilizers and the like. Cocaine type addicting drugs are exemplified by cocaine, xe2x80x9ccrackxe2x80x9d (cocaine in ready-to-smoke form) and the like. Amphetamine type addicting drugs are exemplified by amphetamine, methamphetamine and the like. Cannabis type addicting drugs are exemplified by marijuana (THC), hashish and the like. Hallucinogen type addicting drugs are exemplified by LSD-25, mescaline, psilocibin and the like. Organic solvent type addicting drugs are exemplified by toluene, acetone, carbon tetrachloride and the like (xe2x80x9cOpioidxe2x80x9d, p. 118-120, Kagakudojin, 1991).
It was reported that 1,4-(diphenylalkyl)piperazine derivatives, which are active ingredients of the present invention, have a strong affinity for the xcexa3 receptor and are useful as therapeutic agents for cerebral nerve dysfunctions such as dementia, depression, schizophrenia and anxiety neurosis; diseases accompanied by immune disorders and cryptorrhea; digestive ulcer and the like (Japanese Laid-open Patent Publication No. 89949/1995). It was reported that such derivatives are useful as preventive or therapeutic agents for ophthalmopathy, particularly retinal diseases such as diabetic retinopathy and occlusion of retinal vessels and glaucoma, since such derivatives exhibit protective actions on retinal nerve cells (Japanese Laid-open Patent Publication No. 120569/1998).
Heretofore, a study of the drug dependence of the 1,4-(diphenylalkyl)piperazine derivatives was not done, and it is a very interesting subject.
Studying precisely in order to find new pharmacological actions of 1,4-(diphenylalkyl)piperazine derivatives, the present inventors found that the 1,4-(diphenylalkyl)piperazine derivatives exhibit inhibitory actions on drug dependence. Namely, the present inventors found that the 1,4-(diphenylalkyl)piperazine derivatives are useful as preventive or therapeutic agents for drug dependence due to drug abuse.
The present invention relates to a method for preventing or treating drug dependence comprising administering to a human in need thereof (such as a human having a drug dependency) a pharmaceutically effective amount of a compound represented by the following formula [I] or a salt thereof as active ingredients: 
wherein R1 is lower alkoxy, R2 is lower alkoxy, xe2x80x9cAxe2x80x9d is lower alkylene and xe2x80x9cBxe2x80x9d is lower alkylene.
The groups defined above are described in more detail as follows. The lower alkoxy is lower alkoxy having one to six carbon atoms such as methoxy, ethoxy, propoxy or butoxy. The lower alkylene is lower alkylene having one to six carbon atoms such as methylene, ethylene, propylene or butylene.
Preferred examples of the compound are compounds wherein each group is the following in the compounds represented by the formula [I] or salts thereof:
(1a) xe2x80x9cAxe2x80x9d is lower alkylene having two to four carbon atoms; and/or
(2a) xe2x80x9cBxe2x80x9d is lower alkylene having two to four carbon atoms.
Namely,
Compounds defined by above (1a) in the compounds represented by the formula [I] or salts thereof,
Compounds defined by above (2a) in the compounds represented by the formula [I] or salts thereof, and
Compounds defined by a combination of above (1a) and above (2a) in the compounds represented by the formula [I] or salts thereof.
Particularly preferred examples of the compound are compounds wherein each group is the following in the compounds represented by the general formula [I] or salts thereof;
(1b) R1 is methoxy; and/or
(2b) R is methoxy.
Namely,
Compounds defined by above (1b) in the compounds represented by the formula [I] or salts thereof,
Compounds defined by above (2b) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by a combination of above (1b) and above (2b) in the compounds represented by the general formula [I] or salts thereof.
Examples of particularly preferred compounds are 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl) piperazine represented by the following formula [II] or salts thereof. 
The above-mentioned salts can be pharmaceutically acceptable salts, and are exemplified by hydrochlorides, sulfates, phosphates, lactates, maleates, fumarates, oxalates and the like. The above-mentioned compounds can take the form of hydrates.
The present invention can widely be applied to the drug dependence due to drug abuse and is not limited to specific drug dependence.
As a method of calibrating the existence or the intensity of the potential of drugs to induce psychological dependence, a method has been used since olden times in which selective intake behavior or self-intake behavior toward test drugs is observed. In recent years, as a relatively simple and reliable method, a method wherein effects on conditioned place preference are indexed (CPP method) is applied (xe2x80x9cOpioidxe2x80x9d, p. 118-120, Kagakudojin, 1991). The present inventors studied the existence or the intensity of the potential of addicting drugs to induce psychological dependence in the presence of the 1,4-(diphenylalkyl)piperazine derivatives by using this conditioned place preference test method (CPP method). Details are described in xe2x80x9cPharmacological Testsxe2x80x9d hereinbelow. It is found that the 1,4-(diphenylalkyl)piperazine derivatives exhibit excellent inhibitory effects on the potential of addicting drugs to induce psychological dependence and are useful for the prevention or the treatment of drug dependence due to the abuse of addicting drugs.
Examples of dosage forms of the drugs are oral preparations such as tablets, capsules and granules, injections and the like. These preparations can be prepared by general techniques. For example, in order to prepare oral preparations such as tablets, capsules and granules, the compound [I] or salts thereof can be formulated into the preparations, if necessary, by adding an extending agent such as lactose, starch, crystalline cellulose or vegetable oil, a lubricant such as magnesium stearate or talc, a binder such as hydroxypropylcellulose or polyvinyl pyrrolidone, a disintegrator such as calcium carboxymethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol or a silicone resin, or a gelatin film forming agent.
The dosage is appropriately adjusted depending on symptoms, age, dosage form, type of drug dependence and the like, and in the case of the oral preparations, the usual daily dosage is 1 to 1000 mg, which can be given in a single dose or several divided doses.
Pharmacological Tests are shown below as Examples.
Pharmacological Tests
Effects of 1,4-(diphenylalkyl)piperazine derivatives on the potency of induction of psychological dependence by addicting drugs were studied by using the conditioned place preference test (CPP method) according to the report of Suzuki et al. (Life Science, 57, 1277-1284 (1995)).